Chronic administration of leptin increases arterial pressure through renal sympathetic activation. Renal denervation substantially attenuates obesity induced hypertension.The ability of leptin to increase renal sympathetic nerve activity (SNA)and arterial pressure is preserved in two murine models of obesity despite resistance to the appetite suppressant action of leptin suggesting that leptin could contribute to hypertension in obesity despite resistance to its appetite suppressant actions. The focus of this project is on the hypothalamic molecular leptin signaling pathways mediating selective leptin actions and specifically renal SNA and arterial pressure versus appetite suppressant responses. We have demonstrated that the renal SNA responses to leptin are mediated through PI3 kinase. In contrast, based on preliminary studies, we will test the hypothesis that hypothalamic STAT3 and MAP, while mediating appetite suppressant effectsof leptin, are not involved in leptin induced increases in renal SNA and arterial pressure. Thus, disrupting leptin induced STAT3 or MAP kinase signaling would attenuate the appetite suppressant actions of leptin while preserving the renal SNA and arterial pressure responses. Based on this hypothesis, resistance to the effects of leptin on STATS and MAPK signaling in obesity could promote obesity induced hypertension. We will combine two complementary approaches to evaluate the role of STATS and MAP kinase on renal SNA and arterial pressure responses to leptin: 1) study of obese mouse models with gene targeted disruption of Shp 2 that mediates leptin induced MAP kinase activation or of leptin STATS signaling; and 2) study of mice with conditional "floxed" alleles allowing site specific deletion of STATS, MAP kinase or the leptin receptor using targeted viral microinjections of Cre recombinase into the arcuate nucleus. A distinctive strength of this project is a constellation of highly interactive investigators who can assure the successful application of a combination of robust cardiovascular, neurophysiologic and genetic strategies to advance understanding of the role of leptin signaling pathways in regulation of renal SNA and arterial pressure. Insight into mechanisms of leptin actions on the sympathetic nervous system and arterial pressure should shed insight into cardiovascular complications of obesity.